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R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage

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Item Type:Article
Title:R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage
Creators Name:Chatzidoukaki, O. and Stratigi, K. and Goulielmaki, E. and Niotis, G. and Akalestou-Clocher, A. and Gkirtzimanaki, K. and Zafeiropoulos, A. and Altmüller, J. and Topalis, P. and Garinis, G.A.
Abstract:How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue architecture, and chronic pancreatitis in mice with an inborn defect in the excision repair cross complementation group 1 (Ercc1) gene. We find that DNA damage-driven R-loops causally contribute to the active release and buildup of single-stranded DNAs (ssDNAs) in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or ribonuclease H nucleases in inflamed Ercc1(−/−) pancreatic cells. Treatment of Ercc1(−/−) animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration, Ercc1(−/−) paving the way for novel rationalized intervention strategies against age-related chronic inflammation.
Keywords:Cytoplasm, DNA Damage, DNA Repair, Single-Stranded DNA, DNA-Binding Proteins, Endonucleases, Inflammation, R-Loop Structures, Animals, Mice
Source:Science Advances
Publisher:American Association for the Advancement of Science
Page Range:eabj5769
Date:19 November 2021
Official Publication:https://doi.org/10.1126/sciadv.abj5769
PubMed:View item in PubMed

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